Schizophrenia patients experience severe cognitive dysfunctions but the most prevalent and functionally debilitating are those in verbal episodic memory. Neuroimaging studies have found that abnormal physiological activity in the hippocampus contributes to episodic memory dysfunctions in schizophrenia patients. The hippocampus is known to retain plasticity into adulthood, due to ongoing neurogenesis and synaptic plasticity occurring in the dentate gyrus. Neuroplasticity in schizophrenia patients has been shown to be enhanced with regular physical activity and also by cognitive skills training. What remains to be established is what effect exercise and cognitive training have on neural activity in the episodic memory system in schizophrenia patients and what neurochemical mechanisms are facilitating enhanced neuroplasticity in schizophrenia. Consistent with the NIMH Strategic Plan 1.4, this K01 project seeks to define, measure, and link basic biological and behavioral components of abnormal functioning in a diseased state to clarify the underlying causes of mental disorders. The present study will seek to identify neurobiological mechanisms contributing to increased neuroplasticity in schizophrenia by studying 30 first-episode schizophrenia patients who are participating in an exercise and cognitive training intervention, as compared to 30 in a treatment as usual comparison group. Measures will focus on an episodic memory functional MRI (fMRI) paradigm and neurotrophic factors linked to neuroplasticity. To achieve the training needed to facilitate this investigation, the applicant has consulted with clinical neuropsychologists as well as an integrative exercise physiologist, a translational neuroscientist, an expert in neural repair, and a biostatistician with expertise in longitudinal neuroimaging to develop an innovative study and training plan. The plan will have the following Aims: 1) apply high-resolution structural MRI to measure cortical thickness in the dentate gyrus, which is hypothesized to increase as a result of this intervention; 2) measure neural activity during a verbal episodic memory fMRI task, which is hypothesized to increase in the intervention group; and 3) measure serum levels of neurotrophic growth factors which are neurochemical mechanisms hypothesized to contribute to increased plasticity in the dentate gyrus and improve episodic memory in the intervention group. Collectively, these results will elucidate the neurobiological pathways by which an exercise and cognitive training intervention impact episodic memory functioning in first- episode schizophrenia patients. These experiences will provide the applicant critical training in translational and basic neuroscience along with integrative exercise physiology and biology to link the various mechanisms implicated in the pathology in the disease. The proposed study will provide the applicant the necessary training needed to conduct randomized clinical trials in a psychosis patient sample to detect changes at molecular and neural systems levels to aid in the development of effective cognitive enhancement treatments in schizophrenia. PUBLIC HEALTH RELEVANCE: In addition to the personal, social and medical costs to an individual diagnosed with schizophrenia, the economic cost of treatment of schizophrenia in the U.S. alone is estimated to be $62.7 billion; however, these standard treatments do not target the debilitating cognitive impairments that limit everyday functioning of those with the illness. We propose to use cutting-edge MRI and neurochemical analyses to elucidate the mechanisms of enhanced neuroplasticity and cognition in first-episode schizophrenia patients who are undergoing an innovative combined exercise and cognitive training intervention, compared to patients receiving treatment-as-usual. This multi-disciplinary study will be crucial for identifyin underlying neural substrates that contribute to improved cognition in schizophrenia patients to aid in the development of effective cognitive enhancement treatments in schizophrenia.